Author(s): Kiranmai Gudimetla, Orsu Prabhakar, Abhisek Pal


DOI: 10.5958/0974-360X.2020.00526.0   

Address: Kiranmai Gudimetla1*, Orsu Prabhakar2, Abhisek Pal1
1GITAM School of Pharmacy, GITAM Deemed to be University, Hyderabad, Telangana.
2GITAM Institute of Pharmacy, GITAM Deemed to be University, Visakhapatnam, Andhra Pradesh.
*Corresponding Author

Published In:   Volume - 13,      Issue - 6,     Year - 2020

Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell malignant clonal disorder resulting in elevation of erythroid cells and platelets in peripheral blood and clear myeloid hyperplasia in the bone marrow. Philadelphia (Ph) chromosome detection forms the major diagnosis in CML. It displays the translocation t(9; 22) that generates the oncogene bcr/abl. Constitutive tyrosine kinase activity is been exhibited by the oncoprotein (BCR/ABL) which supports growth and continued existence in cells of CML. Incidence remains almost constant worldwide and it is the most commonest in India majorly in adults. Clinically, Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) are the three phases of CML. The drugs used in the treatment of CML are known as Tyrosine Kinase Inhibitors (TKI’S). The primary drug which directly target BCR-ABL tyrosine kinase activity was Imatinib. Imatinib resistance is the major drawback of this drug due to mutations. Imatinib binding is prevented by BCR-ABL kinase domain mutations, BCR-ABL gene amplification or over-expression, clonal progression, and reduced bioavailability of imatinib or cell exposure. Stem cell transplantation is the only curative approach till date. In patients who cannot undergo transplantation, the BCR-ABL tyrosine kinase inhibitor STI571 (Gleevec, Imatinib), immune therapy or interferon-alpha and other cytoprotective drugs are used. Currently available data shows that Imatinib is a better compound compared to second line drugs in producing complete molecular and cytogenetic responses. The resistance against STI571 has been reported which has to be tested with mutational analysis for the treatment for using an accurate regimen. Current researchers are consequently challenging to inhibit or work against STI571 resistance by the development of new molecules or combination of molecules contributing for further improvement in the treatment of CML and for better understanding of resistant mechanisms. These strategies, whether will guide to curative treatment in CML in the future remains unclear.

Cite this article:
Kiranmai Gudimetla, Orsu Prabhakar, Abhisek Pal. Review on Pathophysiological and Pharmacotherapeutic approach on Chronic Myeloid Leukemia. Research J. Pharm. and Tech 2020; 13(6): 2971-2976. doi: 10.5958/0974-360X.2020.00526.0

Kiranmai Gudimetla, Orsu Prabhakar, Abhisek Pal. Review on Pathophysiological and Pharmacotherapeutic approach on Chronic Myeloid Leukemia. Research J. Pharm. and Tech 2020; 13(6): 2971-2976. doi: 10.5958/0974-360X.2020.00526.0   Available on:

1.    Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960; 132:1497, abstract.
2.    Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243:290-3.
3.    Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7:441–53.
4.    Melo JV, Deininger MW. Biology of chronic myelogenous leukemia--signaling pathways of initiation and transformation. Hematol Oncol Clin North Am. 2004; 18(3):545-68, vii-viii.
5.    Cortes J. Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004; 18(3):569-84
6.    Alvarez RH, Jantarjian H, Cortes JE. The biology of chronic myelogenous leukemia: implications for imatinibe therapy. Semin Hematol. 2007; (1 Suppl 1):S4-S14.
7.    Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005; 5(3):172-83.
8.    Kantarjian HM, Giles F, Cardama AQ, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007; 13(4):1089-97.
9.    Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med 1999; 341:16472.
10.    Hehlmann R. How I treat CML blast crisis. Blood. 2012; 120:737–47.
11.    Leis JF, Primack SL, Schubach SE, Curtin PT, Druker BJ, Maziarz RT. Management of life-threatening pulmonary leukostasis with single agent imatinib mesylate during CML myeloid blast crisis. Haematologica. 2004; 89:ECR30.
12.    Jabbour E, Kantarjian H, O’Brien S, Rios MB, Abruzzo L, Verstovsek S, Garcia-Manero G, Cortes J. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood. 2006; 107:480–2.
13.    AiDI, LiuW, LuG, PatelKP, ChenZI.Extramedullary blast crisis as initial presentation in chronic myeloid leukemia with the e1a2 BCR-ABL1 transcript: a case report. Mol Clin Oncol. 2015; 3:1319–22.
14.    Mohd Ridzuan MS, Yap E, Wan Fariza WJ, Fadilah SA, Salwati S. A case of chronic myeloid leukaemia in blast transformation with leukemic ascites. Med J Malaysia. 2016; 71:85–7.
15.    Gale RP, Horowitz MM, Ash RC, et al. Identical-twin bone marrow transplants for leukemia. Annals of internal medicine. 1994; 120(8):646–652. [PubMed: 8135448]
16.    O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994–1004.
17.    Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355:2408–17.
18.    White DL, Dang P, Engler J, et al. Functional Activity of the OCT-1 Protein Is Predictive of LongTerm Outcome in Patients With Chronic-Phase Chronic Myeloid Leukemia Treated With Imatinib. Journal of Clinical Oncology. 2010; 28(16):2761–2767. [PubMed: 20421539]
19.    Gleysteen JP, Newman JR, Chhieng D, Frost A, Zinn KR, Rosenthal EL. Fluorescent labeled anti-EGFR antibody for identification of regional and distant metastasis in a preclinical xenograft model. Head and Neck-Journal for the Sciences and Specialties of the Head and Neck 2008; 30: 782-89.
20.    Lahaye T, Riehm B, Berger U, et al. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: A 4.5-year follow-up. Cancer 103: 659-669, 2005.
21.    Jabbour E, Kantariian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 20: 1767-1773, 2006.
22.    Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCRABL mutations. Blood 114: 4944-4953, 2009.
23.    Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80.
24.    White DL, Saunders VA, Dang P, Frede A, Eadie L, Soverini S, et al. CML patients with low OCT-1 activity achieve better molecular responses on high dose imatinib than on standard dose. Those with high OCT-1 activity have excellent responses on either dose: a TOPS correlative study [abstract]. Blood. 2008; 112(11):1093-4.
25.    Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, et al. Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst. 2000; 92(20):1641-50.
26.    Meyn MA 3rd, Wilson MB, Abdi FA, Fahey N, Schiavone AP, Wu J, et al. Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate BcrAbl transforming activity. J Biol Chem. 2006; 281(41):30907-16.
27.    Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006; 20(10):1767-73.
28.    Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clinical lymphoma, myeloma & leukemia. 2014; 14(2):155–162. e151.
29.    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004; 305(5682):399-401.
30.    Shah NP, Kim DW, Kantarjian HM, Rousselot P, Dorlhiac-Llacer PE, Milone JH, et al. Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: one-year results of CA180034 [abstract]. J Clin Oncol. 2007; 25(18S): Abstract 7004.
31.    Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009; 113(25):6322-9.
32.    Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005; 7(2):129-41.
33.    Golemovic M, Verstovsek S, Giles F, Cortes J, Manshouri T, Manley PW, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005; 11(13):4941-7.
34.    Kantarjian H, Giles F, Wunderle L, Bhalla K, OBrien S, Wassmann B, et al. Nilotinib inimatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006; 354(24):2542-51.
35.    Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007; 110(10):3540-6.
36.    Plosker GL, Robinson DM. Nilotinib. Drugs. 2008; 68(4):449-59; discussion 460-1.
37.    Deininger MW. Nilotinib. Clin Cancer Res. 2008; 14(13):4027-31.
38.    Kantarjian H, Giles F, Bhalla K, Pinilla-Ibarz J, Larson RA, Gattermann N, et al. Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: clinical response, safety, and long-term outcomes [abstract]. Blood. 2009; 114(22):464.
39.    Bosulif (bosutinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 January 2014.`
40.    Wolff NC, Richardson JA, Egorin M, Ilaria RL Jr. The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood. 2003; 101(12):5010– 5013. [PubMed: 12595307]
41.    Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008; 22(12):2176– 2183. [PubMed: 18754032]
42.    Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013; 27(1):107–112. [PubMed: 22763385]
43.    Gambacorti-Passerini C, Kantarjian HM, Kim D-W, et al. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. American journal of hematology. 2015 Jun 1. [Epub ahead of print].
44.    Mahon FX, Re´a D, Guilhot J et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010; 11: 1029–1035.
45.    Hochhaus A, Masszi T, Giles FJ et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia 2017; 31: 1525–1531.

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